GABAergic modulation of noradrenaline release in the median preoptic nucleus area in the rat

Microdialysis was employed to investigate whether gamma-aminobutyric acid (GABA) receptor mechanisms are involved in the regulation of noradrenaline (NA) release in the median preoptic nucleus (MnPO) in awake, freely moving rats. Perfusion with the GABA receptor antagonists as well as agonists was performed in the region of the MnPO through a microdialysis probe and dialysate levels of NA were measured. Perfusion with either bicuculline (10 and 50 microM), a GABA(A) receptor antagonist, or phaclofen (10 and 50 microM), a GABA(B) receptor antagonist, enhanced the release of NA in the MnPO area. Higher-dose perfusion with the GABA(A) agonist muscimol (50 microM) or the GABA(B) agonist baclofen (250 microM) decreased dialysate NA in the MnPO area. An iso-osmotic reduction of fluid volume following subcutaneous treatment with polyethylene glycol (PEG, 30%, 5 ml) significantly increased the NA level in the MnPO area. The increased levels of NA caused by the PEG treatment were attenuated by perfusion with muscimol (10 microM), but not by baclofen (50 microM). These results show the participation of both GABA(A) and GABA(B) receptors in the modulation of the release of NA in the MnPO area, and imply that the GABA(A) receptor mechanism may play an important role in the noradrenergic regulatory system of body fluid balance.     

Pharmacological investigation on the role of dopamine in the rat locus coeruleus

The role of dopamine (DA) in the rat locus coeruleus (LC) was investigated by determining the levels of 3,4-dihydroxyphenylacetic acid (DOPAC), DA and noradrenaline (NA) in the LC after pharmacological treatments by pargyline, haloperidol, 6-hydroxydopamine (6-OHDA) and desmethylimipramine (DMI). The DA, DOPAC and NA contents of the LC were determined by high pressure liquid chromatography. Fifteen days after 6-OHDA, the DOPAC and NA levels were reduced by 60%, but they remained constant after 6-OHDA + DMI. Pargyline provoked highly significant increases in DA and NA but reduced DOPAC to non-measurable amounts. Haloperidol caused a 54% decrease in the DOPAC levels. Pargyline and haloperidol administered to rats having received 6-OHDA + DMI 15 days before, caused similar effects on DA, DOPAC and NA levels as those in non-treated rats. It is suggested that DOPAC is mainly located in noradrenergic neurons, thus eliminating the possibility of a significant DA cell body population in the rat LC.     

Subfornical organ efferents enhance extracellular noradrenaline concentrations in the median preoptic area in rats

The present study was carried out to examine whether angiotensinergic pathways from the subfornical organ (SFO) regulate the noradrenergic system in the median preoptic nucleus (MnPO). Intracerebral microdialysis techniques were used to quantify the extracellular concentration of noradrenaline (NA) in the MnPO area. In urethane-anesthetized male rats, electrical stimulation (5–20 Hz, 0.6 mA) of the SFO significantly increased the NA concentration in the MnPO area, and the increase was significantly diminished by pretreatment with the angiotensin II (ANG II) antagonist saralasin (Sar; 5 μg), into the third ventricle (3V). Injections of ANG II (5 μg) into the 3V significantly enhanced NA release in the MnPO area. The data imply that the angiotensinergic pathways from the SFO to the MnPO may act to enhance NA release in the MnPO area.     

Atrial natriuretic factor, urinary catechol compounds and electrolyte excretion in rats during normal hydration and isotonic volume expansion. Influence of dopamine receptor blockade

To investigate the influence of acute isotonic volume expansion (VE) on the plasma concentration of atrial natriuretic factor (ANF), the excretion of catechol compounds and electrolytes and the whole kidney glomerular filtration rate (GFR), these variables were measured before and during 60 min of VE (2% of body weight per hour). Atrial natriuretic factor was measured at the end of the experiment. In a control group (n = 7) without volume expansion, plasma ANF was 58 +/- 4 pg ml-1. The excretion of sodium, dopamine (DA), 3,4-dihydroxyphenylacetic acid (DOPAC), noradrenaline (NA) and GFR did not change during the control study. In VE animals (n = 7) plasma ANF was 82 +/- 7 pg ml-1, significantly higher than in the control group. Sodium excretion increased more than 17-fold. The excretion of the DA increased by 38% and that of DOPAC by 30%. Noradrenaline excretion remained unchanged while GFR increased by 20%. In haloperidol-pretreated animals subjected to VE (n = 7), plasma ANF was 81 +/- 8 pg ml-1 during VE, significantly higher than in the control animals. Although the sodium excretion increased more than ninefold in this group during VE, this increase was only 55% of that in the VE group not given haloperidol. The DA and DOPAC excretion was increased by haloperidol, indicating a feedback effect of receptor blockade. DOPAC excretion was not increased further by VE, but the excretion of DA increased by 15% and GFR increased by 19%.(ABSTRACT TRUNCATED AT 250 WORDS)     

Fate of the catecholamine stores in the rabbit carotid body superfused in vitro

In rabbit carotid bodies (CBs) superfused during 1–5 h, with an air-equilibrated medium containing no tyrosine (TYR), the dopamine (DA) content decreased by approximately 60% after 1 h and remained constant afterwards. TYR and 3,4-dihydroxyphenylacetic acid (DOPAC) decreased with the same time course. Noradrenaline (NA) content exhibited a biphasic decrease of lesser magnitude than that of DA. Superfusions with a TYR-containing medium did not prevent the reduction in DA and TYR. Large amounts of DA and DOPAC were recovered in the effluent during the first hour of superfusion but after 90 min the two substances had declined below the detection limits (i.e. 0.5 and 1 pmol/5 min, respectively). The DA efflux decreased exponentially during the first hour and was not altered by changing the oxygen partial pressure (PO₂) of the medium. The DOPAC efflux declined after 40 min of superfusion and was modulated byPO₂. The DA and the DOPAC effluxes were not suppressed by omitting calcium ions from the superfusing medium. In 4 cat CBs equal amounts of DA and NA were recovered from the effluent during the first hour of superfusion.     

Comparison of the monoamine and catabolite content in the cat and rabbit carotid bodies

The monoamine and catabolite contents of a large number of rabbit (n = 95) and cat (n = 32) carotid bodies (CBs) have been measured by high performance liquid chromatography with electrochemical detection (HPLC-ED). The dopamine (DA) content as well as that of its precursors tyrosine (TYR), dihydroxyphenylalanine (DOPA) and catabolites dihydroxyphenylacetic acid (DOPAC), homovanilic acid (HVA) were approximately equal in both species. The noradrenaline (NA) content was 10 times larger in the cat than in the rabbit CBs. Twenty-nine out of the 32 cat CBs contained more NA than DA while the reverse was true in 92 out of 95 rabbit CBs. In 11 cats the right CB was sympathectomized and its DA and NA contents were compared to those of intact contralateral organs.     

The long-term effects of neurotoxic doses of methamphetamine on the extracellular concentration of dopamine measured with microdialysis in striatum.

The extracellular concentrations of dopamine (DA), dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), and 5-hydroxyindoleacetic acid (5-HIAA) in the striatum were measured by in vivo microdialysis in freely moving rats one week after the animals were treated with neurotoxic doses of methamphetamine. Methamphetamine produced a marked depletion of striatal DA measured in postmortem tissue, and in the extracellular concentrations of DOPAC, HVA and 5-HIAA. In contrast, the resting extracellular concentration of DA in striatum was the same as in saline-pretreated controls. Furthermore, methamphetamine-pretreated rats were able to increase their concentration of extracellular DA to the same extent as controls in response to a (+)-amphetamine challenge. It is suggested that this adaptive response is probably responsible, at least in part, for the absence of obvious behavioral deficits in animals exposed to neurotoxic doses of methamphetamine.     

Effect of sex and age on brain monoamines and spatial learning in rats

The concentrations of noradrenaline (NA), dopamine (DA), serotonin (5-HT), and their metabolites were measured in the prefrontal cortex, caudate-putamen, and hippocampus in young (3 months) and aged (27–31 months) Wistar rats of both sexes. Age-related changes were found in prefrontal NA and HVA/DA ratio, striatal DA and DOPAC/DA ratio, and striatal and hippocampal 5-HT and 5-HIAA/5-HT ratio. Age and sex dependent changes were found in striatal DA and DOPAC/DA ratio, and hippocampal MHPG-SO₄/NA ratio. The aged rats were tested in spatial discrimination and reversal tasks in a T maze. The effects of α₂-agonist medetomidine (3 μg/kg) on the task performance were assessed in relation to individual variation in monoamine metabolism. Medetomidine impaired spatial discrimination learning of the aged rats by interacting with the hippocampal 5-HT turnover. Medetomidine improved reversal learning through an interaction with the striatal DA turnover and reduced the number of perseverative errors after reversal, mainly due to its interaction with the prefrontal NA turnover. It is concluded that the memory enhancing effect of drugs acting through the brain monoamine systems is highly dependent on the stage of degeneration of these systems that show considerable individual variation in aged animals.     

The neurotoxic actions of 1-methyl-4-phenylpyridine (MPP+) are not prevented by deprenyl treatment

1-Methyl-4-phenylpyridine (MPP+) injected into the cerebral ventricles (ICV) of mouse caused depletions of striatal dopamine (DA)(-42%), 3,4-dihydroxyphenylacetic acid (DOPAC) (-34%) and homovanillic acid (HVA) (-16%) content without significant reductions in levels of noradrenaline (NA), serotonin (5-HT) or 5-hydroxyindoleacetic acid (5-HIAA). When deprenyl was administered before MPP+, striatal DA and its metabolites were further depleted, and striatal NA and 5-HT levels also were reduced. Further, whilst ICV MPP+ alone failed to influence the biochemistry of the limbic areas (nucleus accumbens plus tuberculum olfactorium), in the presence of deprenyl MPP+ caused 20-40% reductions in levels of limbic NA, DA, DOPAC, HVA, 5-HT and 5-HIAA. Therefore, deprenyl treatment does not prevent the neurotoxic actions of MPP+; indeed, a more extensive neurotoxicity for MPP+ is revealed in the presence of this monoamine oxidase inhibitor.     

Functional in vivo interaction between growth hormone and dopamine systems are correlated to changes in striatal somatostatin levels as detected by voltammetry

The effects of growth hormone (GH) and somatomedin C (SmC), as well as those of apomorphine, dopamine (DA) agonist, or haloperidol (DA antagonist), upon the size of striatal voltammetric peaks 2 and 5 were investigated. Local intrastriatal injections of GH or SmC were followed by an increase in the height of both peak 2 (corresponding to the oxidation of extracellular dihydro-phenylacetic acid, DOPAC, a metabolite of DA) and peak 5 (which may represent the oxidation of striatal extracellular somatostatin, SRIF). Treatment with haloperidol also increased the size of the striatal catechol peak but was responsible for a reduction of the neuropeptidergic signal. By contrast, apomorphine determined a decrease in striatal peak 2 (DOPAC) while increasing the levels of peak 5 (SRIF). The data further support the chemical identification of peak 5 at +800 mV as related to the in vivo oxidation of SRIF; in addition they indicate the presence of a functional relationship between this neuropeptide and the GH and DA systems in the striatum of anaesthetised rats.     

Differential effects of L-trytophan and buspirone on biogenic amine contents and metabolism in Lurcher mice cerebellum

The effects of serotoninergic stimulation on monoamines were studied in the heterozygous Lurcher (Lc/+) mutant mouse, a model of human cerebellar ataxia. Wild type (+/+) and Lc/+ mice were treated for 40 days with L-tryptophan or buspirone, and serotonin (5-HT), dopamine (DA), noradrenaline (NA) and their main metabolites were measured in the cerebellum. In +/+ mice, only buspirone increased concentrations of 5-HT metabolites. In the hypoplastic Lc/+ cerebellum, indoleamines were higher, and increased further after both treatments. The 5-HT turnover index was increased in +/+ mice by buspirone, while in Lc/+ mutants it increased after L-tryptophan but was decreased by buspirone, indicating that in the mutants nerve terminals synthesize and accumulate 5-HT, but may not utilize it efficiently. Catecholamine contents remained unchanged in +/+ mice, but in Lc/+ mutants with higher endogenous NA, L-tryptophan further increased NA and 3,4-dihydroxy-phenylacetic acid (DOPAC), and buspirone augmented NA, DA and DOPAC levels.     

Evidence that the neuronal nitric oxide synthase inhibitor 7-nitroindazole inhibits monoamine oxidase in the rat: in vivo effects on extracellular striatal dopamine and 3,4-dihydroxyphenylacetic acid.

The present study investigated in vivo the kinetic of the changes in rat striatal extracellular concentrations of dopamine (DA), and its monoamine oxidase (MAO)-derived metabolite 3,4-dihydroxyphenylacetic acid (DOPAC), following administration either of nitric oxide (NO) synthase (NOS) inhibitors 7-nitroindazole (7-NI) and Nomega-nitro-l-arginine methyl ester (L-NAME) or of the widely used MAO inhibitor pargyline. DA and DOPAC concentrations were determined every 4 min by microdialysis combined with capillary zone electrophoresis coupled with laser-induced fluorescence detection (CZE-LIFD) and by differential normal pulse voltammetry (DNPV), respectively. Administration of 7-NI, both systemic (30 mg/kg, intraperitoneally, i.p.) or intrastriatal (1 mM through the microdialysis probe), as well as administration of pargyline (75 mg/kg, i.p.), induced simultaneously in the striatum a significant increase in extracellular DA and a significant decrease in extracellular DOPAC. However, administration of L-NAME (200 mg/kg, i.p.) produced a significant increase in striatal extracellular DA without changes in extracellular DOPAC. These data suggest a possible MAO inhibitory effect of 7-NI which seems to be restricted to this NOS inhibitor. These results may be of special interest for the studies on functional role of NO in the brain, particularly in dopaminergic transmission.     

Presynaptic ionotropic glutamate receptors modulate in vivo release and metabolism of striatal dopamine,noradrenaline, and 5-hydroxytryptamine: involvement of both NMDA and AMPA/kainate subtypes

In order to explore further the presynaptic modulation of monoamine release by glutamatergic nerve fibers, we investigated the effects of selective agonists for ionotropic glutamate (GLU) receptors on striatal release of dopamine (DA), noradrenaline (NA) and 5-hydroxytryptamine (5-HT). In the striatum of anesthetized Sprague-Dawley rats, in vivo microdialysis was performed to measure the release of monoamines and metabolites, and also to administer GLU agonists locally in the tissue. l-GLU and its selective agonists (N-methyl-d-aspartate (NMDA), α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) and kainate (KA)) evoked simultaneous release of striatal DA, NA and 5-HT in a dose-dependent manner. Pretreatment with MK-801 (5 mg/kg i.p.), a noncompetitive NMDA receptor antagonist, selectively suppressed NMDA-evoked monoamine release. The rank order of GLU agonist efficacy in releasing monoamines was different among DA, NA, and 5-HTergic terminals: AMPA = KA > NMDA for DA release, AMPA > NMDA = KA for NA release, and NMDA = AMPA = KA for 5-HT release. In conclusion, presynaptic ionotropic GLU receptors exist extensively on monoaminergic terminals including not only catecholaminergic (DA and NA) but also indoleaminergic (5-HT) terminals in the rat striatum. Their subtypes include both NMDA subtype and AMPA/KA subtype, and show a differential distribution among these three monoaminergic terminals and a differential contribution to facilitating monoamine release.     

Iptakalim alleviated the increase of extracellular dopamine and glutamate induced by 1-methyl-4-phenylpyridinium ion in rat striatum

The present study examined the effect of iptakalim (Ipt), a novel ATP-sensitive potassium (K(ATP)) channel opener (KCO), on 1-methyl-4-phenylpyridinium ion (MPP(+))-induced dopamine (DA) and glutamate efflux in extracellular fluid of rat striatum, using microdialysis technique. Rats were implanted guide cannula in the striatum and artificial cerebrospinal fluid was infused through a microdialysis probe to detect the level of DA and glutamate in the striatum. MPP(+) significantly enhanced the extracellular levels of DA and its metabolites, DOPAC and HVA, as well as glutamate. Application of Ipt (1, 10, 100 microM) concentration-dependently suppressed DA and its metabolites efflux induced by MPP(+). Concomitantly, Ipt reduced the increase of extracellular glutamate induced by MPP(+). These results suggest that Ipt can regulate DA and glutamate efflux induced by MPP(+) in rat striatum.     

Phencyclidine increases extracellular dopamine metabolites in rat medial frontal cortex as measured by in vivo dialysis

An acute intraperitoneal injection of phencyclidine (PCP) caused a tetrodotoxin-reversible increase in extracellular release of 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) in the dialysates from the medial frontal cortex of the rat. Moreover, there was an increase in the tissue content of DOPAC and HVA with acceleration of dopamine (DA), but not noradrenaline, utilization in the cortical area after systemic administration of PCP. These results suggest that PCP facilitates DA metabolism in the medial frontal cortex by increasing impulse flow in the DA neurons projecting to the prefrontal region.     

Efferent projections from the median preoptic nucleus to sleep- and arousal-regulatory nuclei in the rat brain

The median preoptic nucleus (MnPO) has been implicated in the regulation of hydromineral balance and cardiovascular regulation. The MnPO also contains neurons that are active during sleep and in response to increasing homeostatic pressure for sleep. The potential role of these neurons in the regulation of arousal prompted an analysis of the efferent projections from the MnPO. Anterograde and retrograde neuroanatomical tracers were utilized to characterize the neural connectivity from the MnPO to several functionally important sleep- and arousal-regulatory neuronal systems in the rat brain. Anterograde terminal labeling from the MnPO was confirmed within the core and extended ventrolateral preoptic nucleus. Within the lateral hypothalamus, labeled axons were observed in close apposition to proximal and distal dendrites of hypocretin/orexin immunoreactive (IR) cells. Projections from the MnPO to the locus coeruleus were observed within and surrounding the tyrosine hydroxylase-IR cell cluster. Labeled axons from the MnPO were mostly observed within the lateral division of the dorsal raphé nucleus and heavily within the ventrolateral periaqueductal gray. Few anterogradely labeled appositions were present juxtaposed to choline acetyltransferase-IR somata within the magnocellular preoptic area. The use of retrogradely transported neuroanatomical tracers placed within the prospective efferent terminal fields supported and confirmed findings from the anterograde tracer experiments. These anatomical findings support the hypothesis that MnPO neurons function to promote sleep by inhibition of orexinergic and monoaminergic arousal systems and disinhibition of sleep regulatory neurons in the ventrolateral preoptic area.     

Evidence that the neuronal nitric oxide synthase inhibitor 7-nitroindazole inhibits monoamine oxidase in the rat: in vivo effects on extracellular striatal dopamine and 3,4-dihydroxyphenylacetic acid

The present study investigated in vivo the kinetics of the changes in rat striatal extracellular concentrations of dopamine (DA), and its monoamine oxidase (MAO)-derived metabolite 3,4-dihydroxyphenylacetic acid (DOPAC), following administration either of nitric oxide (NO) synthase inhibitors 7-nitroindazole (7-NI) and N(omega)-nitro-L-arginine methyl ester (L-NAME) or of the widely used MAO inhibitor pargyline. DA and DOPAC concentrations were determined every 4 min by microdialysis combined with capillary zone electrophoresis coupled with laser-induced fluorescence detection (CZE-LIFD) and by differential normal pulse voltammetry (DNPV), respectively. Administration of 7-NI, both systemic (30 mg/kg, i.p.) or intrastriatal (1 mM through the microdialysis probe), as well as administration of pargyline (75 mg/kg, i.p.), induced simultaneously in the striatum a significant increase in extracellular DA and a significant decrease in extracellular DOPAC. On the other hand, administration of L-NAME (200 mg/kg, i.p.) produced a significant increase in striatal extracellular DA without changes in extracellular DOPAC. These data suggest a possible MAO inhibitory effect of 7-NI which seems to be restricted to this NOS inhibitor. These results may be of special interest for the studies on the functional role of NO in the brain, particularly in dopaminergic transmission.     

Effects of thienorphine on release of dopamine and noradrenalin: an in vivo microdialysis study in rats

Thenorphine is a new potent long-acting partial opioid agonist. In present study, the effect of thienorphine on noradrenalin (NA) in the locus coeruleus (LC) and dopamine (DA) and its metabolites in the nucleus acumbens (NAc) and the striatum were examined in freely moving rats during acute and chronic thienorphine treatment followed by naloxone-precipitated withdrawal using the in vivo microdialysis technique. Acute thienorphine (1.0mg/kg, s.c.) treatment had no effect on the level of NA in the LC and the level of DA in the NAc and the striatum. Chronic thienorphine (1.0mg/kg, s.c.) third per day for continued 5 days treatment followed by naloxone-precipitated (5.0mg/kg, i.p.) had not alter the extracellular NA level in the LC and the extracellular level of DA in the NAc and the striatum, but significantly increased the level of DOPAC in the striatum. These changes are thought to reflect a direct effect of thienorphine on release of NA and DA. Thus thienorphine deserves further study as a new treatment for opioid dependence.     

Comparison of the effects of intracerebrally administered MPP+ (1-methyl-4-phenylpyridinium) in three species: microdialysis of dopamine and metabolites in mouse, rat and monkey striatum

Intracerebral microdialysis in 3 awake species allowed the measurement of the basal output of dopamine (DA), dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA) and 5-hydroxyindole-acetic acid (5-HIAA) from rat and mouse striatum and monkey caudate in vivo. The DOPAC/HVA ratios in dialysates from mouse and rat striatum were about 1 and 2 respectively, but only 0.09 in monkey caudate dialysates. The extracellular levels of the metabolites correlated well with reported tissue levels, while extracellular DA levels were 3 orders of magnitude lower than tissue concentrations. The effects of the intracerebrally administered dopaminergic neurotoxin 1-methyl-4-phenylpyridinium (MPP+) were essentially similar in the 3 species. In all cases an immediate, massive release of DA was accompanied by a pronounced decrease in the output of the metabolites. Basal DA release was no longer detectable 5-12 h after MPP+ administration and a second MPP+ perfusion failed to increase the release of DA.     

The effect of acute and repeated ethanol administration on monoamines and their metabolites in brain regions of rats

Concentrations of norepinephrine (NE), dopamine (DA), 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), serotonin (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) were determined in eleven brain regions of rats following acute and repeated ethanol administration: (a) an intraperitoneal (i.p.) injection of 1, 2, 3 or 4g ethanol/kg body weight and (b) i.p. injection of 1 or 2g ethanol/kg body weight for seven consecutive days. After acute administration, the concentrations of monoamines and their metabolites appeared to be altered in all brain regions examined except substantia nigra and dorsal amygdala, with maximal variation 2 or 3h after 3g ethanol administration. After repeated administration, the alterations following injections of 2.0g/kg were more marked than the injections of 1.0g/kg. Generally, the levels of NE, DA and 5-HT were decreased while the levels of HVA, DOPAC and 5-HIAA were increased with a few exception. The most prominent findings were seen in the striatum, nucleus accumbens and locus coeruleus. These data indicate that concentrations of monoamines and their metabolites can be determined simultaneously in discrete brain regions and that monoaminergic systems in the brain respond region-specifically to ethanol treatment.